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Biomedical subjects

K Rogers

Publications and source records attributed to K Rogers.

At least 19 recordsLinked to original sources
PubMed2000

Integrated sample collection and handling for drug discovery bioanalysis.

An integrated sample handling process for drug discovery bioanalysis is described. The streamlining of study design, sample collection and automatic bioanalytical sample processing is demonstrated. Specific details for the entire procedure regarding the time saved, ease of automation and integration are defined. Details of sample handling involved a sample collection map, sample collection formatting and volume, dilution schemes for high concentration samples, choice of biological fluid and evaluating the capabilities of two liquid-handling workstations. Numerous comparisons were conducted between the new approaches and the conventional sample handling approaches. The precision and accuracy obtained from the new integrated sample handling process were comparable to those obtained from a conventional approach, as were pharmacokinetic profiles and parameters. This new sampling process greatly improved the efficiency of drug discovery bioanalysis. The integration of pre-clinical protocol design, sample collection and bioanalysis processes was also achieved.

Animals↗
PubMed1999

Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor.

FK506-binding protein (FKBP12) has been found to be associated with the skeletal muscle ryanodine receptor (RyR1) (calcium release channel), whereas FKBP12.6, a novel isoform of FKBP, is selectively associated with the cardiac ryanodine receptor (RyR2). For both RyRs, the stoichiometry is 4 FKBP/RyR. Although FKBP12.6 differs from FKBP12 by only 18 of 108 amino acids, FKBP12.6 selectively binds to RyR2 and exchanges with bound FKBP12.6 of RyR2, whereas both FKBP isoforms bind to RyR1 and exchange with bound FKBP12 of RyR1. To assess the amino acid residues of FKBP12.6 that are critical for selective binding to RyR2, the residues of FKBP12.6 that differ with FKBP12 were mutated to the respective residues of FKBP12. RyR2 of cardiac sarcoplasmic reticulum, prelabeled by exchange with [35S]FKBP12.6, was used as assay system for binding/exchange with the mutants. The triple mutant (Q31E/N32D/F59W) of FKBP12.6 was found to lack selective binding to the cardiac RyR2, comparable with that of FKBP12.0. In complementary studies, mutations of FKBP12 to the three critical amino acids of FKBP12.6, conferred selective binding to RyR2. Each of the FKBP12.6 and FKBP12 mutants retained binding to the skeletal muscle RyR1. We conclude that three amino acid residues (Gln31, Asn32, and Phe59) of human FKBP12.6 account for the selective binding to cardiac RyR2.

Amino Acid Sequence↗
PubMed1999

An important role for major histocompatibility complex class I-restricted T cells, and a limited role for gamma interferon, in protection of mice against lethal herpes simplex virus infection.

Herpes simplex virus (HSV) inhibits major histocompatibility complex (MHC) class I expression in infected cells and does so much more efficiently in human cells than in murine cells. Given this difference, if MHC class I-restricted T cells do not play an important role in protection of mice from HSV, an important role for these cells in humans would be unlikely. However, the contribution of MHC class I-restricted T cells to the control of HSV infection in mice remains unclear. Further, the mechanisms by which these cells may act to control infection, particularly in the nervous system, are not well understood, though a role for gamma interferon (IFN-gamma) has been proposed. To address the roles of MHC class I and of IFN-gamma, C57BL/6 mice deficient in MHC class I expression (beta2 microglobulin knockout [beta2KO] mice), in IFN-gamma expression (IFN-gammaKO mice), or in both (IFN-gammaKO/beta2KO mice) were infected with HSV by footpad inoculation. beta2KO mice were markedly compromised in their ability to control infection, as indicated by increased lethality and higher concentrations of virus in the feet and spinal ganglia. In contrast, IFN-gamma appeared to play at most a limited role in viral clearance. The results suggest that MHC class I-restricted T cells play an important role in protection of mice against neuroinvasive HSV infection and do so largely by mechanisms other than the production of IFN-gamma.

Animals↗
PubMed1999

Retrospective report on the effectiveness of a polyurethane football helmet cover on the repeated occurrence of cerebral concussions.

This report reviews the literature and unpublished data and presents survey results related to the use of a polyurethane football helmet cover. Two hundred forty-five individuals, identified by the helmet manufacturer as having purchased at least one device, were sent a survey after the 1992, 1993, and 1994 football seasons; 155 (63.3%) of the surveys were returned. The questionnaire, designed to be completed by the athlete, required a detailed history of concussions occurring both prior to and during the period the device was used. Individuals used the device as a result of having incurred at least one concussion. Rates of concussion reoccurrence while the device was worn were grouped by the number of previous concussions (1, 2, 3, or 4+) that occurred over a 4year period prior to use of the device. The rate of concussion reoccurrence was 2.4%, 7.3%, 15.8%, and 33.3%, respectively, over a 4-year period. The range appeared to reflect a parallel relationship between pre- and post-device concussion experiences: the more concussions experienced prior to adopting the device, the higher the rate of concussion reoccurrence while using the device. The natural history of repeated occurrences of concussive events may not be affected by the use of a polyurethane football helmet cover. We suggest that such a device not be routinely used prophylactically, but instead be reserved for individuals with 1 to 2 prior concussion injuries. However, at this time, we neither recommend nor discommend the device.

Adolescent↗
PubMed1998

Doxorubicin induced expression of P-glycoprotein in a canine osteosarcoma cell line.

Canine and human osteosarcoma are very similar with respect to clinical presentation, radiological and histopathological features, metastatic rate and pattern and response to therapy. For these reasons, canine osteosarcoma is a useful intermediate model for the disease in humans. Overexpression of P-glycoprotein, the product of the MDR1 gene, is the most important predictor of an adverse clinical course in human patients with osteosarcoma. Exposure of canine osteosarcoma cells to doxorubicin resulted in overexpression of MDR1 mRNA and P-glycoprotein. Furthermore, these cells failed to accumulate doxorubicin intracellularly and were less sensitive to vincristine-induced cytotoxicity as compared to parental cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Identification and localization of extracellular Ca(2+)-sensing receptor in rat intestine.

The extracellular calcium (Ca2+o)-sensing receptor (CaR) plays vital roles in Ca2+o homeostasis, but no data are available on its expression in small and large intestine. Polymerase chain reaction products amplified from reverse-transcribed duodenal RNA using CaR-specific primers showed > 99% homology with the rat kidney CaR. Northern analysis with a CaR-specific cRNA probe demonstrated 4.1- and 7.5-kb transcripts in all intestinal segments. Immunohistochemistry with CaR-specific antisera showed clear basal staining of epithelial cells of small intestinal villi and crypts and modest apical staining of the former, whereas there was both basal and apical staining of colonic crypt epithelial cells. In situ hybridization and immunohistochemistry also demonstrated CaR expression in Auerbach's myenteric plexus of small and large intestines and in the submucosa in the region of Meissner's plexus. Our results reveal CaR expression in several cell types of small and large intestine, in which it may modulate absorptive and/or secretomotor functions.

Animals↗
PubMed1997

Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors.

The amyloid-beta peptides (A beta) are produced in excess in Alzheimer's disease (AD) and may contribute to neuronal dysfunction and degeneration. This study provides strong evidence for a novel cellular target for the actions of A beta, the phospholipase C-coupled, extracellular Ca(2+)-sensing receptor (CaR). We demonstrate that A beta(s) produce a CaR-mediated activation of a Ca(2+)-permeable, nonselective cation channel (NCC), probably via elevation in cytosolic Ca2+ (Cai), in cultured hippocampal pyramidal neurons from normal rats and from wild type mice but not those from mice with targeted disruption of the CaR gene (CaR -/-). A beta(s) also activate NCC in CaR-transfected but not in nontransfected human embryonic kidney (HEK293) cells. Thus aggregates of A beta deposited on hippocampal neurons in AD could appropriately activate the CaR, stimulating Ca(2+)-permeable channels and causing sustained elevation of Cai with resultant neuronal dysfunction.

Amyloid beta-Peptides↗
PubMed1997

Plexosarcoma of the bladder.

Plexosarcomas are rare soft tissue sarcomas, previously reported in association with gastrointestinal autonomic nerve (GAN) plexi. We report the first case arising from the autonomic nerve plexus of the bladder.

Humans↗
PubMed1997

Tardive dyskinesia exacerbated after ingestion of phenylalanine by schizophrenic patients.

Despite continued research, the influences that promote or exacerbate tardive dyskinesia (TD) symptoms remain incompletely understood. Recent findings (Gardos et al. 1992; Richardson et al. 1989) suggest that ingestion of the dietary constituent, phenylalanine, might exacerbate TD symptoms, but a double-blind, placebo-controlled challenge had not previously been conducted in schizophrenic patients. On two different mornings, in counterbalanced order, 18 male schizophrenic patients with TD were challenged with either 100 mg/kg phenylalanine or placebo. Effects on abnormal involuntary movements, recall memory, and plasma phenylalanine were measured 90 minutes post-challenge. The results supported the hypothesis in that involuntary movements increased to a statistically and clinically meaningful degree after the phenylalanine challenge, but not after placebo. No effects on memory were detected. Significant order effects characterized the plasma findings but not the behavioral data. Results indicate that a dietary constituent, the amino acid phenylalanine, can potentially exacerbate tardive dyskinesia symptoms in schizophrenic patients. The influence of phenylalanine and other ingested substances on clinical symptomatology warrants further investigation.

Adult↗
PubMed1997

Skin appendage involvement in anal intraepithelial neoplasia.

BACKGROUND: High-grade anal intraepithelial neoplasia (AIN III) may be premalignant. Surgical excision of large areas of anal epithelium carries significant morbidity. Ablation treatments may carry less morbidity; however, the depth of ablation is uncertain and failure to ablate dysplasia in hair shafts and other skin appendages may lead to early recurrence. METHODS: This study assesses morphometric aspects of skin appendages in perianal skin and anal canal mucosa in tissues from 30 patients with AIN III. Both normal and dysplastic epithelium was assessed in each patient. The depth to which AIN III involved skin appendages was measured using computerized image analysis. RESULTS: Both the perianal epidermis and anal canal mucosa affected by AIN III were significantly thicker than normal. Nineteen of 30 patients with AIN III had skin appendage involvement. Some 57 per cent of hair follicles (79 of 138), 16 per cent of sebaceous glands (11 of 69) and 25 per cent of sweat glands (24 of 96) observed beneath an abnormal epithelium had evidence of AIN. The median depth of AIN involvement of the hair follicle was 1.14 (range 0.44-1.67) mm, sebaceous glands 1.44 (range 0.96-1.90) mm, and sweat glands 0.94 (range 0.50-2.20) mm. These figures do not take into account tissue shrinkage due to histological processing. CONCLUSION: AIN III involvement of epithelial appendages is a significant problem. For disease eradication, tissue destruction or removal to a depth of at least 2.2 mm below the adjacent basement membrane is required. Surgical excision of high-grade AIN remains the treatment of choice.

Adult↗
PubMed1997

Squamous cell carcinoma originating from a cutaneous scar in a llama.

A nonhealing wound associated with a laceration in a 12-year-old llama was evaluated. Initial attempts at closure were unsuccessful and biopsy revealed scar tissue. Subsequent biopsies, 18 mo later, revealed squamous cell carcinoma with regional metastasis. This report describes squamous cell carcinoma, secondary to a traumatic wound in a llama.

Animals↗
PubMed1996

Agonists of the Ca(2+)-sensing receptor (CaR) activate nonselective cation channels in HEK293 cells stably transfected with the human CaR.

Calcium (Ca2+) ions serve multiple roles both intra- and extracellularly. We recently cloned a cell surface, Cao(2+)-sensing receptor (CaR) that plays a central role in Cao2+ homeostasis by enabling direct regulation by Cao2+ of parathyroid hormone (PTH) secretion and the function of other tissues involved in mineral ion homeostasis. In parathyroid cells, the CaR activates phospholipase C, thereby raising the levels of inositol trisphosphate (IP3) and releasing Ca2+ from intracellular stores. High Cao2+ also activates Ca2+ influx into parathyroid cells through poorly defined mechanisms that may involve Ca(2+)-permeable, nonselective cation channels (NCC). We now show that human embryonic kidney (HEK293) cells also have NCC and, furthermore, that these channels are regulated by the CaR. We have utilized the cell-attached configuration of the patch clamp technique to characterize the properties of these channels as well as their regulation by various CaR agonists added to the external bath solution. The polycationic CaR agonist, neomycin (100 microM), as well as an elevated concentration of Cao2+ (3 mM), both of which activate the cloned CaR, significantly increased the probability of channel opening (Po) in HEK cells stably transfected with the CaR but not in nontransfected HEK cells which do not contain the receptor. Thus, the activation of the CaR enhances the activity of Ca(2+)-permeable NCC in these cells, which could contribute to the sustained increase in Cai2+ in parathyroid cells which is observed in response to elevated Cao2+. The CaR may also regulate the membrane functions of other CaR-expressing cells (e.g., those in the brain), at least in part, by modulating similar channels.

Calcium-Binding Proteins↗
PubMed1996

Escherichia coli tryptophanyl-tRNA synthetase mutants selected for tryptophan auxotrophy implicate the dimer interface in optimizing amino acid binding.

Tryptophan auxotrophs of Escherichia coli in which mutations were mapped to the trpS locus (encoding tryptophanyl-tRNA synthetase) have been previously isolated. We have investigated the tryptophanyl-tRNA synthetase (TrpRS) purified from six auxotrophic strains for changes in amino acid activation and aminoacylation. Steady-state kinetic analyses show that these mutant TrpRS proteins have increases in the apparent KM for tryptophan, decreases in turnover number, or both, without significant changes in the apparent KM for ATP or tRNA(Trp). The crystal structure of a highly homologous tryptophanyl-tRNA synthetase from Bacillus stearothermophilus in a complex with the cognate aminoacyl adenylate allowed us to place the mutations in a structural context. The mutations in the enzymes are located in the KMSKS loop (M196I), in or near the active site (D112E, P129S, A133E) or far from the active site. The last three mutants (T60R, L91F, G329S) could not be predicted by examination of the protein structure as they line an interface between the C-terminal alpha-helix of one subunit and the Rossmann folds of both subunits, thus affecting a specific region of the dimer interface. These results support a role for dimerization in properly configuring the two active sites of the dimeric enzymes in the Trp/Tyr subclass of class I aminoacyl-tRNA synthetases in order to achieve optimal catalysis.

Amino Acid Sequence↗
PubMed1996

Pharmacokinetics of pyropheophorbide-a-hexyl ether in the dog.

BACKGROUND AND OBJECTIVES: Pyropheophorbide-a-hexyl ether (HPPH) is a new compound being investigated for use as a photosensitizer for photodynamic therapy; however, the pharmacokinetics are not known for any of the target species likely to be treated with this drug. The objective of this study was to determine the pharmacokinetic parameters of this drug prior to institution of a clinical trial in canine patients with various cancers. STUDY DESIGN, MATERIALS AND METHODS: HPPH (0.3mg/kg i.v.) was administered to 12 dogs and blood samples were drawn at intervals for 24 hours and plasma HPPH concentrations were determined. Pharmacokinetic parameters were calculated for each dog. RESULTS: No evidence of toxicity was noted in any dog. The mean half-life was calculated to be 26.98 +/- 2.35 hrs. The mean clearance was 5.061 +/- 0.214 ml/hr/kg. The mean volume of distribution of the central compartment was 0.069 +/- 0.003 L/kg, and the mean steady state volume of distribution was 4.47 +/- 0.25 L/kg. CONCLUSION: The conclusion is that 0.3 mg/kg HPPH injected intravenously resulted in measurable plasma levels for 24 hrs, and resulted in no detectable adverse reactions.

Animals↗
PubMed1996

Effect of syringe size on bruising following subcutaneous heparin injection.

BACKGROUND: Bruising and induration associated with subcutaneous heparin injection often result in sustained tenderness and severe ecchymosis at the injection site. Research-based practice guidelines for subcutaneous heparin administration are needed to reduce these adverse effects. OBJECTIVES: The purpose of this study was to investigate the effect of syringe size (1-mL vs 3-mL) on postinjection-site bruising and induration following the administration of subcutaneous heparin. METHODS: A convenience sample of 29 subjects receiving 5000 units of subcutaneous heparin at least twice a day was recruited from a large urban hospital. Subjects received their regularly scheduled subcutaneous heparin injections with a 3-mL or a 1-mL syringe in a randomized sequence using a standardized procedure. Injection sites were assessed for bruises and induration at 24, 48, and 72 hours after injection. RESULTS: The incidence of injection site bruising with 1- and 3-mL syringes was 79% and 69%, respectively. The use of a 3-mL vs 1-mL syringe resulted in significantly smaller bruises at 48 and 72 hours after injection. Induration at the injection site occurred in three patients. CONCLUSIONS: Findings suggest that 3-mL syringes are preferable to 1-mL syringes for heparin administration. The effect of other injection-related variables should be studied with the use of the 3-mL syringe, and tested on various populations.

Adult↗
PubMed1995

Radical surgery for advanced and recurrent breast cancer.

Locally advanced or recurrent breast cancer is commonly seen in breast clinics. One method of palliation for ulcerating tumours is a radical mastectomy with replacement of the chest wall defect with a myocutaneous flap. We report on our experience of this technique in the management of 35 women (21 advanced disease, 14 recurrent disease). The perioperative complications were minimal and there are some longterm survivors. 15 women are alive and well (range 20-96 months postoperatively, mean 55 months). This radical surgery, therefore, has a significant role in the management of selected women with breast cancer.

Adult↗